Investigations into the origin of the molecular recognition of several adenosine deaminase inhibitors

J Med Chem. 2011 Jan 13;54(1):107-21. doi: 10.1021/jm101286g. Epub 2010 Dec 7.

Abstract

Inhibitors of adenosine deaminase (ADA, EC 3.5.4.4) are potential therapeutic agents for the treatment of various health disorders. Several highly potent inhibitors were previously identified, yet they exhibit unacceptable toxicities. We performed a SAR study involving a series of C2 or C8 substituted purine-riboside analogues with a view to discover less potent inhibitors with a lesser toxicity. We found that any substitution at C8 position of nebularine resulted in total loss of activity toward calf intestinal ADA. However, several 2-substituted-adenosine, 8-aza-adenosine, and nebularine analogues exhibited inhibitory activity. Specifically, 2-Cl-purine riboside, 8-aza-2-thiohexyl adenosine, 2-thiohexyl adenosine, and 2-MeS-purine riboside were found to be competitive inhibitors of ADA with K(i) values of 25, 22, 6, and 3 μM, respectively. We concluded that electronic parameters are not major recognition determinants of ADA but rather steric parameters. A C2 substituent which fits ADA hydrophobic pocket and improves H-bonding with the enzyme makes a good inhibitor. In addition, a gg rotamer about C4'-C5' bond is apparently an important recognition determinant.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemical synthesis
  • Adenosine / chemistry*
  • Adenosine Deaminase / chemistry*
  • Adenosine Deaminase Inhibitors / chemical synthesis
  • Adenosine Deaminase Inhibitors / chemistry*
  • Animals
  • Aza Compounds / chemical synthesis
  • Aza Compounds / chemistry*
  • Cattle
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Molecular Conformation
  • Purine Nucleosides / chemical synthesis
  • Purine Nucleosides / chemistry*
  • Ribonucleosides / chemical synthesis
  • Ribonucleosides / chemistry*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Adenosine Deaminase Inhibitors
  • Aza Compounds
  • Purine Nucleosides
  • Ribonucleosides
  • nebularine
  • Adenosine Deaminase
  • Adenosine